Roughly one-third of the non-olfactory GPCRs in the human genome are 'orphans' whose endogenous or natural ligands are unknown, with many more understudied (ie., `dark') from a chemical perspective. This represents an enormous gap in our understanding of human health and disease. This has particular relevance for mental illness since many orphan GPCRs are enriched in the brain and associated with neurological conditions, suggesting they play critical (patho)physiological roles. To test this hypothesis, Dr. Strachan will identify small molecule tools to modulate the functions of candidate brain-enriched orphan receptors GPR85, GPRC5B, GPR123, and GPR162. Working closely with his mentoring team, Dr. Strachan will develop new expertise in areas of robotic high throughput screening, multidisciplinary drug discovery (ie., medicinal chemistry, cheminformatics, and computational screening), and mouse genetics that he will carry over to his own independent research career establishing the (patho)physiology of these orphan GPCRs. The insight gained here has the potential to establish new signaling paradigms in the brain, thus exposing new therapeutic avenues for treating seemingly intractable psychiatric diseases. In addition to the implications for patient mental health, this K01 provides an uncommon training environment for Dr. Strachan to mature as a productive faculty member and to acquire new expertise in cutting-edge academic drug discovery techniques, genetic strategies, and neurobiology. Dr. Strachan's strong background in molecular pharmacology will synergize with the skills he acquires here to position him for a successful independent research career investigating the therapeutic potential of brain-enriched orphan receptors.